The sustained release of active agents from drug delivery devices, for example, in the form of an ocular insert, tablet, transdermal patch, or implantable device is well known. In the administration of certain pharmaceuticals, long-term drug delivery has been shown to be effective in that constant serum levels are obtained and patient compliance is improved. Delaying the release of the active agent is also desirable in that an immediate release upon placement in the delivery environment can result in unacceptably high initial concentrations of a drug at the sites of implantation.
The examination of synthetic hydrogels for potential biomedical applications (including potential use in certain drug delivery devices) has given rise to various theories regarding mechanisms of diffusion. Lee, Jhon and Andrade have proposed that there are three classes of water in hydrogels, using poly(2-hydroxyethyl methacrylate), oftentimes abbreviated as polyHEMA, as their model [Nature of Water in Sythetic Hydrogels, J. Colloid & Interface Sci., 51 (2): 225-231 (1975)]. The first 20% of hydrogel water content, called "Z water", was said to be bound to the polymer matrix. The next 10-12% of water content, called interfacial or "Y water", is partially affected by the polymer matrix. Any additional water imbibed by the gel is relatively unaffected by the polymer matrix; it is called bulk or "X water".
The Lee, et al. model was expanded upon by Kim, Cardinal, Wisniewski and Zentner [Solute Permeation Through Hydrogel Membranes: Hydrophilic vs. Hydrophobic Solutes, ACS Symposium Series (Water in Polymers), 127 (20): 347-359 (1980)]. They concluded that the diffusion coefficients for hydrophilic solutes through hydrogel membranes depends on molecular size and water content; permeation in pure polyHEMA and in polyHEMA crosslinked with a low mole percent of ethylene glycol dimethacrylate was via the pore mechanism, i.e., through the bulk-type water. Hydrophobic solutes were said to diffuse via both pore and partition mechanisms, i.e., respectively through the bulk-type water, and through the interfacial-type and bound-type water.
Wood, Attwood and Collett have described a model for diffusion of the small hydrophobic molecule salicylic acid (the solute) in hydrogels [The Influence of Gel Formulation on the Diffusion of Salicylic Acid in PolyHEMA Hydrogels, J. Pharm. Pharmacol., 34: 1-4 (1982)]. Radioactively labeled salicylic acid was added to a HEMA monomer solution and polymerized in situ. The water contents of the resulting gels were measured. Diffusion was measured by quantifying migration of the solute to a gel placed in contact with the sample gels. It was concluded that diffusion occurred primarily through the polymer's pores via the hydrating liquid at higher levels of hydration (more than 31%). At hydration levels below 31%, diffusion was said to occur by dissolution of the solute within the polymer segments; crosslinker concentration did not have any significant effect on diffusion. This was correlated to a change in pore size proportional with percent hydration. For another treatment of the interaction of pore size and diffusion, see Wisniewski and Kim [J. Membrane Sci., 6: 299-308 (1980)].
Microporous membranes (some including hydrogels) have been used as rate-limiting barriers for such devices, including implants, ocular inserts, coated intrauterine devices and the like, for example, as described in U.S. Pat. Nos. 3,416,530, 3,618,604, and 3,828,777 to Ness; U.S. Pat. No. 3,551,556 to Kliment, et al; U.S. Pat. No. 4,548,990 to Mueller, et al.
In U.S. Pat. Nos. 3,993,072, 3,948,254, and 3,854,380 to Zaffaroni, drug delivery systems are disclosed including a solid inner matrix containing a drug and surrounded by a wall formed of a polymeric membrane (the '072 and '254 patents call for a microporous membrane, the pores of which contain a drug-release-rate-controlling medium).
Some sustained release devices have been described for the delivery of hydrophilic macromolecules, such as polypeptides. For example, European Patent Application Publication No. 0,092,918 to Churchill, et al. entitled "Continuous Release Formulations" describes the continuous release of, e.g., luteinizing hormone-releasing hormone, growth hormones and growth hormone releasing factor, from a hydrophobic/hydrophilic noncrosslinked copolymer in which the hydrophobic component is biodegradable and the hydrophilic component may or may not be biodegradable. The composition is described as being capable of absorbing water to form a hydrogel when placed in an aqueous, physiological-type environment.
In European Patent Application Publication No. 0246653, publication date Nov. 25, 1987, in the names of Sanders and Domb there is disclosed a drug delivery device comprising a pharmaceutically acceptable carrier, macromolecules of at least 1,000 molecular weight mixed with said carrier, and a partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane, such as crosslinked poly(2-hydroxyethyl methacrylate), which surrounds or envelops the drug and carrier. The examples disclose a cylindrical reservoir-type delivery device formed by polymerizing a mixture of 2-hydroxyethyl methacrylate (HENU) and ethylene glycol dimethaciylate (EGDMA) in a cylindrical mold, with or without a core. When a mold without a core is used, a core is drilled into the cylindrical polymer matrix. The reservoir is then filled with an amount of suspended drug sufficient to carry out the treatment regimen. A fresh mixture of HESM and EGDMA is added to the top of the reservoir and polymerized to effect a seal.
The patent applicants further disclose the preparation of polymer rods of HEMA/EGDMA using small glass vials (about 3 cm.times.0.6 cm) as the polymerization vessel. After completion of the polymerization reaction, polymer rods (2.5 cm in length and 6.0 mm in diameter) are recovered by breaking the glass vials and they are thereafter placed in a desiccator maintained at a humidity of 23 percent for 6 hours. To fabricate a core (reservoir) in the rods, the patent applicants disclose the following:
"The rods were removed from the desiccator and carefully drilled to form a reservoir having a diameter of 4.0 mm, proceeding with the drill in about 0.5 cm steps, followed by removal of the drill bit from the rod for cooling (by immersion in water or by application of a cold air) before commencing the next 0.5 cm step. Drilling is continued until a reservoir of sufficient volume is formed, in no event drilling closer to the end of the rod than the thickness of the reservoir (i.e., 2.0 mm). It was observed that having the rods in a partially hydrated state was of significant benefit for the drilling operation. Fully hydrated rods were found to be too flexible and soft. Dry rods were found to be too stiff and easy to crack during drilling."
The fabrication of partially hydrated rods, as proposed above, for use in a drug delivery device is quite labor intensive, tedious, and expensive. The drilling procedure, effected in several steps on the small partially hydrated rods, results in a core (the reservoir) whose surface suffers from a lack of uniformity and desired smoothness. Additionally, the thickness between the core surface and the outer surface of the rod would lack uniformity and cause an irregular release rate of the macromolecules. The device thus suffers from poor geometry and is relatively bulky.
Davidson, Domb, Sanders, and McRae disclose that hydrogel membranes of polyHEMA and HEMA/methyl methacrylate copolymer can be used for controlled delivery of analogs of LHRH. Cylindrical implant devices of crosslinked poly(2-hydroxyethyl methacrylate) containing excess LHRH analog (RS-49947) dispersed in silicone oil were implanted in several beagles for one year. Several of the devices, because of the low mechanical strength of the hydrogel polymer, did not remain intact for the whole year; however, of those devices remaining intact estrus was suppressed in the female beagles [Hydrogels for Controlled Release of Peptides, Proceed. Intern. Symp. Cont. Rel. Bioact. Mater., 15, (1988), Controlled Release Society, Inc.].
U.S. Pat. Nos. 4,517,138 and 4,517,139 to Rawlings et al disclose a method for spin casting contact lenses by employing a polymerization tube which is adapted to receive and accommodate a plurality of vertically arranged circular molds in interference fitting relationship. Each mold contains lens-forming material in the mold cavity. The polymerization tube with its interior filled with stacked molds is rotated about its longitudinal axis, maintained perpendicular to the ground, under polymerization conditions. Rotation of the tube will cause the stacked molds to rotate at the same speed while maintaining the concentricity of the molds to the spinning axis of the tube to produce the lenses.